Verma A

References (21)

Title : Design, Synthesis, and Biological Investigation of Quinazoline Derivatives as Multitargeting Therapeutics in Alzheimer's Disease Therapy - Verma_2024_ACS.Chem.Neurosci__
Author(s) : Verma A , Waiker DK , Singh N , Roy A , Saraf P , Bhardwaj B , Krishnamurthy S , Trigun SK , Shrivastava SK
Ref : ACS Chem Neurosci , : , 2024
Abstract : An efficient and promising method of treating complex neurodegenerative diseases like Alzheimer's disease (AD) is the multitarget-directed approach. Here in this work, a series of quinazoline derivatives (AV-1 to AV-21) were rationally designed, synthesized, and biologically evaluated as multitargeted directed ligands against human cholinesterase (hChE) and human beta-secretase (hBACE-1) that exhibit moderate to good inhibitory effects. Compounds AV-1, AV-2, and AV-3 from the series demonstrated balanced and significant inhibition against these targets. These compounds also displayed excellent blood-brain barrier permeability via the PAMPA-BBB assay. Compound AV-2 significantly displaced propidium iodide (PI) from the acetylcholinesterase-peripheral anionic site (AChE-PAS) and was found to be non-neurotoxic at the maximum tested concentration (80 microM) against differentiated SH-SY5Y cell lines. Compound AV-2 also prevented AChE- and self-induced Abeta aggregation in the thioflavin T assay. Additionally, compound AV-2 significantly ameliorated scopolamine and Abeta-induced cognitive impairments in the in vivo behavioral Y-maze and Morris water maze studies, respectively. The ex vivo and biochemical analysis further revealed good hippocampal AChE inhibition and the antioxidant potential of the compound AV-2. Western blot and immunohistochemical (IHC) analysis of hippocampal brain revealed reduced Abeta, BACE-1, APP/Abeta, and Tau molecular protein expressions levels. The pharmacokinetic analysis of compound AV-2 demonstrated significant oral absorption with good bioavailability. The in silico molecular modeling studies of lead compound AV-2 moreover demonstrated a reasonable binding profile with AChE and BACE-1 enzymes and stable ligand-protein complexes throughout the 100 ns run. Compound AV-2 can be regarded as the lead candidate and could be explored more for AD therapy.
ESTHER : Verma_2024_ACS.Chem.Neurosci__
PubMedSearch : Verma_2024_ACS.Chem.Neurosci__
PubMedID: 38327209

Title : Lead optimization based design, synthesis, and pharmacological evaluation of quinazoline derivatives as multi-targeting agents for Alzheimer's disease treatment - Verma_2024_Eur.J.Med.Chem_271_116450
Author(s) : Verma A , Waiker DK , Singh N , Singh A , Saraf P , Bhardwaj B , Kumar P , Krishnamurthy S , Srikrishna S , Shrivastava SK
Ref : Eur Journal of Medicinal Chemistry , 271 :116450 , 2024
Abstract : The complexity and multifaceted nature of Alzheimer's disease (AD) have driven us to further explore quinazoline scaffolds as multi-targeting agents for AD treatment. The lead optimization strategy was utilized in designing of new series of derivatives (AK-1 to AK-14) followed by synthesis, characterization, and pharmacological evaluation against human cholinesterase's (hChE) and beta-secretase (hBACE-1) enzymes. Amongst them, compounds AK-1, AK-2, and AK-3 showed good and significant inhibitory activity against both hAChE and hBACE-1 enzymes with favorable permeation across the blood-brain barrier. The most active compound AK-2 revealed significant propidium iodide (PI) displacement from the AChE-PAS region and was non-neurotoxic against SH-SY5Y cell lines. The lead molecule (AK-2) also showed Abeta aggregation inhibition in a self- and AChE-induced Abeta aggregation, Thioflavin-T assay. Further, compound AK-2 significantly ameliorated Abeta-induced cognitive deficits in the Abeta-induced Morris water maze rat model and demonstrated a significant rescue in eye phenotype in the A-phenotypic drosophila model of AD. Ex-vivo immunohistochemistry (IHC) analysis on hippocampal rat brains showed reduced Abeta and BACE-1 protein levels. Compound AK-2 suggested good oral absorption via pharmacokinetic studies and displayed a good and stable ligand-protein interaction in in-silico molecular modeling analysis. Thus, the compound AK-2 can be regarded as a lead molecule and should be investigated further for the treatment of AD.
ESTHER : Verma_2024_Eur.J.Med.Chem_271_116450
PubMedSearch : Verma_2024_Eur.J.Med.Chem_271_116450
PubMedID: 38701714

Title : Design, synthesis, and biological evaluation of some 2-(3-oxo-5,6-diphenyl-1,2,4-triazin-2(3H)-yl)-N-phenylacetamide hybrids as MTDLs for Alzheimer's disease therapy - Waiker_2024_Eur.J.Med.Chem_271_116409
Author(s) : Waiker DK , Verma A , Gajendra TA , Namrata , Roy A , Kumar P , Trigun SK , Srikrishna S , Krishnamurthy S , Davisson VJ , Shrivastava SK
Ref : Eur Journal of Medicinal Chemistry , 271 :116409 , 2024
Abstract : Inspite of established symptomatic relief drug targets, a multi targeting approach is highly in demand to cure Alzheimer's disease (AD). Simultaneous inhibition of cholinesterase (ChE), beta secretase-1 (BACE-1) and Dyrk1A could be promising in complete cure of AD. A series of 18 diaryl triazine based molecular hybrids were successfully designed, synthesized, and tested for their hChE, hBACE-1, Dyrk1A and Abeta aggregation inhibitory potentials. Compounds S-11 and S-12 were the representative molecules amongst the series with multi-targeted inhibitory effects. Compound S-12 showed hAChE inhibition (IC(50) value = 0.486 +/- 0.047 microM), BACE-1 inhibition (IC(50) value = 0.542 +/- 0.099 microM) along with good anti-Abeta aggregation effects in thioflavin-T assay. Only compound S-02 of the series has shown Dyrk1A inhibition (IC(50) value = 2.000 +/- 0.360 microM). Compound S-12 has also demonstrated no neurotoxic liabilities against SH-SY5Y as compared to donepezil. The in vivo behavioral studies of the compound S-12 in the scopolamine- and Abeta-induced animal models also demonstrated attanuation of learning and memory functions in rats models having AD-like characteristics. The ex vivo studies, on the rat hippocampal brain demonstrated reduction in certain biochemical markers of the AD brain with a significant increase in ACh level. The Western blot and Immunohistochemistry further revealed lower tau, APP and BACE-1 molecular levels. The drosophilla AD model also revealed improved eyephenotype after treatment with compound S-12. The molecular docking studies of the compounds suggested that compound S-12 was interacting with the ChE-PAS & CAS residues and catalytic dyad residues of the BACE-1 enzymes. The 100 ns molecular dynamics simulation studies of the ligand-protein complexed with hAChE and hBACE-1 also suggested stable ligand-protein confirmation throughout the simulation run.
ESTHER : Waiker_2024_Eur.J.Med.Chem_271_116409
PubMedSearch : Waiker_2024_Eur.J.Med.Chem_271_116409
PubMedID: 38663285

Title : Alzheimer's disease: Molecular aspects and treatment opportunities using herbal drugs - Thakral_2023_Ageing.Res.Rev__101960
Author(s) : Thakral S , Yadav A , Singh V , Kumar M , Kumar P , Narang R , Sudhakar K , Verma A , Khalilullah H , Jaremko M , Emwas AH
Ref : Ageing Res Rev , :101960 , 2023
Abstract : Alzheimer's disease (AD), also called senile dementia, is the most common neurological disorder. Around 50 million people, mostly of advanced age, are suffering from dementia worldwide and this is expected to reach 100-130 million between 2040 and 2050. AD is characterized by impaired glutamatergic and cholinergic neurotransmission, which is associated with clinical and pathological symptoms. AD is characterized clinically by loss of cognition and memory impairment and pathologically by senile plaques formed by Amyloid beta deposits or neurofibrillary tangles (NFT) consisting of aggregated tau proteins. Amyloid beta deposits are responsible for glutamatergic dysfunction that develops NMDA dependent Ca(2+) influx into postsynaptic neurons generating slow excitotoxicity process leading to oxidative stress and finally impaired cognition and neuronal loss. Amyloid decreases acetylcholine release, synthesis and neuronal transport. The decreased levels of neurotransmitter acetylcholine, neuronal loss, tau aggregation, amyloid beta plaques, increased oxidative stress, neuroinflammation, bio-metal dyshomeostasis, autophagy, cell cycle dysregulation, mitochondrial dysfunction, and endoplasmic reticulum dysfunction are the factors responsible for the pathogenesis of AD. Acetylcholinesterase, NMDA, Glutamate, BACE1, 5HT6, and RAGE (Receptors for Advanced Glycation End products) are receptors targeted in treatment of AD. The FDA approved acetylcholinesterase inhibitors Donepezil, Galantamine and Rivastigmine and N-methyl-D-aspartate antagonist Memantine provide symptomatic relief. Different therapies such as amyloid beta therapies, tau-based therapies, neurotransmitter-based therapies, autophagy-based therapies, multi-target therapeutic strategies, and gene therapy modify the natural course of the disease. Herbal and food intake is also important as preventive strategy and recently focus has also been placed on herbal drugs for treatment. This review focuses on the molecular aspects, pathogenesis and recent studies that signifies the potential of medicinal plants and their extracts or chemical constituents for the treatment of degenerative symptoms related to AD.
ESTHER : Thakral_2023_Ageing.Res.Rev__101960
PubMedSearch : Thakral_2023_Ageing.Res.Rev__101960
PubMedID: 37224884

Title : Design, Synthesis, and Biological Evaluation of Piperazine and N-Benzylpiperidine Hybrids of 5-Phenyl-1,3,4-oxadiazol-2-thiol as Potential Multitargeted Ligands for Alzheimer's Disease Therapy - Waiker_2023_ACS.Chem.Neurosci__
Author(s) : Waiker DK , Verma A , Akhilesh , Gajendra TA , Singh N , Roy A , Dilnashin H , Tiwari V , Trigun SK , Singh SP , Krishnamurthy S , Lama P , Davisson VJ , Shrivastava SK
Ref : ACS Chem Neurosci , : , 2023
Abstract : Our present work demonstrates the successful design and synthesis of a new class of compounds based upon a multitargeted directed ligand design approach to discover new agents for use in Alzheimer's disease (AD). All the compounds were tested for their in vitro inhibitory potential against human acetylcholinesterase (hAChE), human butylcholinesterase (hBChE), beta-secretase-1 (hBACE-1), and amyloid beta (Abeta) aggregation. Compounds 5d and 5f have shown hAChE and hBACE-1 inhibition comparable to donepezil, while hBChE inhibition was comparable to rivastigmine. Compounds 5d and 5f also demonstrated a significant reduction in the formation of Abeta aggregates through the thioflavin T assay and confocal, atomic force, and scanning electron microscopy studies and significantly displaced the total propidium iodide, that is, 54 and 51% at 50 microM concentrations, respectively. Compounds 5d and 5f were devoid of neurotoxic liabilities against RA/BDNF (RA = retinoic acid; BDNF = brain-derived neurotrophic factor)-differentiated SH-SY5Y neuroblastoma cell lines at 10-80 microM concentrations. In both the scopolamine- and Abeta-induced mouse models for AD, compounds 5d and 5f demonstrated significant restoration of learning and memory behaviors. A series of ex vivo studies of hippocampal and cortex brain homogenates showed that 5d and 5f elicit decreases in AChE, malondialdehyde, and nitric oxide levels, an increase in glutathione level, and reduced levels of pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) mRNA. The histopathological examination of mice revealed normal neuronal appearance in the hippocampal and cortex regions of the brain. Western blot analysis of the same tissue indicated a reduction in Abeta, amyloid precursor protein (APP)/Abeta, BACE-1, and tau protein levels, which were non-significant compared to the sham group. The immunohistochemical analysis also showed significantly lower expression of BACE-1 and Abeta levels, which was comparable to donepezil-treated group. Compounds 5d and 5f represent new lead candidates for developing AD therapeutics.
ESTHER : Waiker_2023_ACS.Chem.Neurosci__
PubMedSearch : Waiker_2023_ACS.Chem.Neurosci__
PubMedID: 37216500

Title : Design and development of benzyl piperazine linked 5-phenyl-1,2,4-triazole-3-thione conjugates as potential agents to combat Alzheimer's disease - Kiran_2023_Bioorg.Chem_139_106749
Author(s) : Kiran PVR , Waiker DK , Verma A , Saraf P , Bhardwaj B , Kumar H , Singh A , Kumar P , Singh N , Srikrishna S , Trigun SK , Shrivastava SK
Ref : Bioorg Chem , 139 :106749 , 2023
Abstract : Our present work demonstrates the molecular hybridization-assisted design, synthesis, and biological evaluation of 22 benzylpiperazine-linked 1,2,4-triazole compounds (PD1-22) as AD modifying agents. All the compounds were tested for their in vitro hChEs, hBACE-1, and Abeta-aggregation inhibition properties. Among them, compound PD-08 and PD-22 demonstrated good hChE and hBACE-1 inhibition as compared to standards donepezil and rivastigmine. Both compounds displaced PI from PAS at 50 microM concentration which was comparable to donepezil and also demonstrated anti-Abeta aggregation properties in self- and AChE-induced thioflavin T assay. Both compounds have shown excellent BBB permeation via PAMPA-BBB assay and were found to be non-neurotoxic at 80 microM concentration against differentiated SH-SY5Y cell lines. Compound PD-22 demonstrated an increase in rescued eye phenotype in Abeta-phenotypic drosophila AD model and amelioration of behavioral deficits in the Abeta-induced rat model of AD. The in-silico docking studies of compound PD-22 revealed a good binding profile towards CAS and PAS residues of AChE and the catalytic dyad of the BACE-1. The 100 ns molecular dynamics simulation studies of compound PD-22 complexed with AChE and BACE-1 enzymes suggested stable ligand-protein complex throughout the simulation run. Based on our findings compound PD-22 could further be utilized as a lead to design a promising candidate for AD therapy.
ESTHER : Kiran_2023_Bioorg.Chem_139_106749
PubMedSearch : Kiran_2023_Bioorg.Chem_139_106749
PubMedID: 37517157

Title : Development and Evaluation of Some Molecular Hybrids of N-(1-Benzylpiperidin-4-yl)-2-((5-phenyl-1,3,4-oxadiazol-2-yl)thio) as Multifunctional Agents to Combat Alzheimer's Disease - Waiker_2023_ACS.Omega_8_9394
Author(s) : Waiker DK , Verma A , Saraf P , T AG , Krishnamurthy S , Chaurasia RN , Shrivastava SK
Ref : ACS Omega , 8 :9394 , 2023
Abstract : A series of some novel compounds (SD-1-17) were designed following a molecular hybridization approach, synthesized, and biologically tested for hAChE, hBChE, hBACE-1, and Abeta aggregation inhibition potential to improve cognition and memory functions associated with Alzheimer's disease. Compounds SD-4 and SD-6 have shown multifunctional inhibitory profiles against hAChE, hBChE, and hBACE-1 enzymes in vitro. Compounds SD-4 and SD-6 have also shown anti-Abeta aggregation potential in self- and acetylcholinesterase (AChE)-induced thioflavin T assay. Both compounds have shown a significant propidium iodide (PI) displacement from the cholinesterase-peripheral active site (ChE-PAS) region with excellent blood-brain barrier (BBB) permeability and devoid of neurotoxic liabilities. Compound SD-6 ameliorates cognition and memory functions in scopolamine- and Abeta-induced behavioral rat models of Alzheimer's disease (AD). Ex vivo biochemical estimation revealed a significant decrease in malonaldehyde (MDA) and AChE levels, while a substantial increase of superoxide dismutase (SOD), catalase, glutathione (GSH), and ACh levels is seen in the hippocampal brain homogenates. The histopathological examination of brain slices also revealed no sign of neuronal or any tissue damage in the SD-6-treated experimental animals. The in silico molecular docking results of compounds SD-4 and SD-6 showed their binding with hChE-catalytic anionic site (CAS), PAS, and the catalytic dyad residues of the hBACE-1 enzymes. A 100 ns molecular dynamic simulation study of both compounds with ChE and hBACE-1 enzymes also confirmed the ligand-protein complex's stability, while quikprop analysis suggested drug-like properties of the compounds.
ESTHER : Waiker_2023_ACS.Omega_8_9394
PubMedSearch : Waiker_2023_ACS.Omega_8_9394
PubMedID: 36936338

Title : Lysosomal Acid Lipase Activity in Non-alcoholic Fatty Liver Disease as a Novel Diagnostic and Therapeutic Target: A Systematic Literature Review of Current Evidence and Future Directions - Bashir_2022_J.Clin.Exp.Hepatol_12_1535
Author(s) : Bashir A , Duseja A , Verma A , De A , Tiwari P
Ref : J Clin Exp Hepatol , 12 :1535 , 2022
Abstract : BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) presents with the accumulation of excessive intra-hepatic fat without significant alcohol intake. Multifactorial pathogenesis is reported to be involved. Reduced lysosomal acid lipase (LAL) activity is suggested as one of the novel-involved pathogenic mechanisms. This review summarizes the available evidence on the role of LAL activity in NAFLD pathogenesis. METHODS: Four databases namely, PubMed/Medline, Science direct, Cochrane Library, and Google scholar were searched to identify relevant observational records evaluating the role of LAL activity in the pathogenesis of NAFLD. All studies were assessed for their quality by using Newcastle-Ottawa Scale or The Joanna Briggs Institute Critical Appraisal tools for cohort and cross-sectional studies, respectively. The estimates of LAL activity and other clinical outcomes were expressed as mean (SD) and number (%) as presented in the primary studies. RESULTS: A total of nine good quality studies with 1711 patients with NAFLD and 877 controls from different groups (healthy volunteers, alcoholics, cryptogenic cirrhosis, and HCV-positive) were included. From the NAFLD group, 59.55% were males and the overall mean age ranged between the studies from 12.6 +/- 8.5 months in pediatrics to 58.90 +/- 13.82 years in adults. In the NAFLD group, the LAL activity varied from 0.53 +/- 0.08 to 1.3 +/- 0.70 (nmol/spot/hr) between the studies which was less than all control groups except cryptogenic cirrhosis patients (0.5 +/- 0.15 nmol/spot/hr). Of the other outcomes of interest, ALT, AST, total cholesterol, triglyceride, and LDL cholesterol were found elevated in NAFLD patients than in controls. CONCLUSION: The current evidence suggests a potential correlation of reduced LAL activity with NAFLD pathogenesis according to its severity. Large-scale studies are recommended, more importantly in patients with NAFLD having no metabolic or genetic involvement. Further LAL can act as a new non-invasive diagnostic biomarker to identify that specific NAFLD subgroup.
ESTHER : Bashir_2022_J.Clin.Exp.Hepatol_12_1535
PubMedSearch : Bashir_2022_J.Clin.Exp.Hepatol_12_1535
PubMedID: 36340307

Title : The molecular mechanism, targets, and novel molecules in the treatment of Alzheimer's disease - Verma_2021_Bioorg.Chem_119_105562
Author(s) : Verma A , Kumar Waiker D , Bhardwaj B , Saraf P , Shrivastava SK
Ref : Bioorg Chem , 119 :105562 , 2021
Abstract : Alzheimer's disease (AD) is a progressive neurological illness that causes dementia mainly in the elderly. The challenging obstacles related to AD has freaked global healthcare system to encourage scientists in developing novel therapeutic startegies to overcome with the fatal disease. The current treatment therapy of AD provides only symptomatic relief and to some extent disease-modifying effects. The current approach for AD treatment involves designing of cholinergic inhibitors, Abeta disaggregation inducing agents, tau inhibitors and several antioxidants. Hence, extensive research on AD therapy urgently requires a deep understanding of its pathophysiology and exploration of various chemical scaffolds to design and develop a potential drug candidate for the treatment. Various issues linked between disease and therapy need to be considered such as BBB penetration capability, clinical failure and multifaceted pathophisiology requires a proper attention to develop a lead candidate. This review article covers all probable mechanisms including one of the recent areas for investigation i.e., lipid dyshomeostasis, pathogenic involvement of P. gingivalis and neurovascular dysfunction, recently reported molecules and drugs under clinical investigations and approved by FDA for AD treatment. Our summarized information on AD will attract the researchers to understand and explore current status and structural modifications of the recently reported heterocyclic derivatives in drug development for AD therapy.
ESTHER : Verma_2021_Bioorg.Chem_119_105562
PubMedSearch : Verma_2021_Bioorg.Chem_119_105562
PubMedID: 34952243

Title : Molecular Docking and Cognitive Impairment Attenuating Effect of Phenolic Compound Rich Fraction of Trianthema portulacastrum in Scopolamine Induced Alzheimer's Disease Like Condition - Yadav_2019_Neurochem.Res_44_1665
Author(s) : Yadav E , Singh D , Debnath B , Rathee P , Yadav P , Verma A
Ref : Neurochem Res , 44 :1665 , 2019
Abstract : Dementia is considered as the frequent cause of neurodegenerative mental disorder such as Alzheimer's disease (AD) amongst elderly people. Free radicals as well as cholinergic deficit neurons within nucleus basalis magnocellularis demonstrated to attribute with aggregation of beta amyloid which further acts as an essential hallmark in AD. Various phenolic phytoconstituents exists in Trianthema portulastrum (TP) leaves have been reported as active against various neurological disorders. The current investigation was undertaken to evaluate the antiamnesic potential of butanol fraction of TP hydroethanolic extract (BFTP) by utilizing rodent models of elevated plus maze (EPM) and Hebbs William Maze (HWM) along with in vitro and in vivo antioxidant as well as acetylcholinesterase (AChE) inhibition studies. Molecular docking studies were also performed for evaluation of molecular interaction of existed phenolic compounds in BFTP. In vitro antioxidant study revealed concentration dependant strong ability of BFTP to inhibit free radicals. In vitro AChE inhibition study showed competitive type of inhibition kinetics. BFTP significantly reversed (p < 0.005 versus scopolamine) the damaging effect of scopolamine by reducing TL (Transfer Latency) and TRC (Time taken to recognize the reward chamber) in the EPM and HWM, respectively. BFTP also contributed towards increased (p < 0.005 versus scopolamine) enzymatic antioxidant as well as hippocampal acetylcholine (ACh) levels. Histological studies also supported the results as BFTP pretreated mice significantly reversed the scopolamine induced histological changes in hippocampal region. Docking studies confirmed chlorogenic acid has the most significant binding affinity towards AChE. This research finding concludes that BFTP could be a beneficial agent for management of cognition and behavioral disorders associated with AD.
ESTHER : Yadav_2019_Neurochem.Res_44_1665
PubMedSearch : Yadav_2019_Neurochem.Res_44_1665
PubMedID: 30949934

Title : Amelioration of neurodegeneration and cognitive impairment by Lemon oil in experimental model of Stressed mice - Falls_2018_Biomed.Pharmacother_106_575
Author(s) : Falls N , Singh D , Anwar F , Verma A , Kumar V
Ref : Biomed Pharmacother , 106 :575 , 2018
Abstract : Citrous lemon (Rutaceae) an Indian folk medicine has been used for the treatment of various pathological diseases viz., diabetes, cardiovascular, inflammation, hepatobiliary dysfunction and neurodegenerative disorder. Can lemon oil altered the memory of unstressed and stressed mice, a basic question for which the present work was put on trial. The present investigation was intended to assess the impact of Lemon oil on memory of unstressed and Stressed Swiss young Albino mice. Lemon oil (50 and 100mg/kg o.r.) and donepezil (10mg/kg) were guided for three weeks to different groups of stressed and unstressed mice. The nootropic movement was assessed utilizing elevated plus maze and Hebbs Williams Maze. Cerebrum acetylcholinesterase (AChE), plasmacorticosterone, decreased glutathione, lipid per oxidation alongside superoxide dismutase and catalase was surveyed as marker for disease. Histopathology was performed for estimation of drug effects. Acute immobilized stress was induce, lemon oil (100mg/kg) and donepezil together indicated memory enhancing movement both in stressed and unstressed mice. Lemon oil significantly (p<0.001) altered and lowered brain AChE activity both in stressed and unstressed mice. Scopolamine induced amnesia was also significantly altered and reversed both in stressed and unstressed mice by lemon oil at a dose of 50 and 100mg/kg. Lemon oil (50 and 100mg/kg) was further able to control the corticosterone level in plasma for stressed mice. Lemon oil significantly (p<0.001) elevated the level of catalase, superoxide dismutase and reduced glutathione levels both in stressed and unstressed animals with respect to controlled group along with TBARS both in stressed and unstressed compared with control group. Hence it can be concluded that memory enhancing activity might be related to reduction in AChE and TBARS activity and by elevated GSH, SOD and catalase through decrease in raised plasma corticosterone levels.
ESTHER : Falls_2018_Biomed.Pharmacother_106_575
PubMedSearch : Falls_2018_Biomed.Pharmacother_106_575
PubMedID: 29990845

Title : Select beta- and gamma-branched 1-alkylpyrazol-4-yl methylcarbamates exhibit high selectivity for inhibition of Anopheles gambiae versus human acetylcholinesterase - Carlier_2018_Pestic.Biochem.Physiol_151_32
Author(s) : Carlier PR , Chen QH , Verma A , Wong DM , Mutunga JM , Muller J , Islam R , Shimozono AM , Tong F , Li J , Totrov M , Bloomquist JR
Ref : Pestic Biochem Physiol , 151 :32 , 2018
Abstract : The widespread emergence of pyrethroid-resistant Anopheles gambiae has intensified the need to find new contact mosquitocides for indoor residual spraying and insecticide treated nets. With the goal of developing new species-selective and resistance-breaking acetylcholinesterase (AChE)-inhibiting mosquitocides, in this report we revisit the effects of carbamate substitution on aryl carbamates, and variation of the 1-alkyl group on pyrazol-4-yl methylcarbamates. Compared to aryl methylcarbamates, aryl dimethylcarbamates were found to have lower selectivity for An. gambiae AChE (AgAChE) over human AChE (hAChE), but improved tarsal contact toxicity to G3 strain An. gambiae. Molecular modeling studies suggest the lower species-selectivity of the aryl dimethylcarbamates can be attributed to a less flexible acyl pocket in AgAChE relative to hAChE. The improved tarsal contact toxicity of the aryl dimethylcarbamates relative to the corresponding methylcarbamates is attributed to a range of complementary phenomena. With respect to the pyrazol-4-yl methylcarbamates, the previously observed low An. gambiae-selectivity of compounds bearing alpha-branched 1-alkyl groups was improved by employing beta- and gamma-branched 1-alkyl groups. Compounds 22a (cyclopentylmethyl), 21a (cyclobutylmethyl), and 26a (3-methylbutyl) offer 250-fold, 120-fold, and 96-fold selectivity, respectively, for inhibition of AgAChE vs. hAChE. Molecular modeling studies suggests the high species-selectivity of these compounds can be attributed to the greater mobility of the W84 side chain in the choline-binding site of AgAChE, compared to that of W86 in hAChE. Compound 26a has reasonable contact toxicity to G3 strain An. gambiae (LC50 = 269 mug/mL) and low cross-resistance to Akron strain (LC50 = 948 mug/mL), which bears the G119S resistance mutation.
ESTHER : Carlier_2018_Pestic.Biochem.Physiol_151_32
PubMedSearch : Carlier_2018_Pestic.Biochem.Physiol_151_32
PubMedID: 30524149

Title : Comparative Evaluation of Prosopis cineraria (L.) Druce and Its ZnO Nanoparticles on Scopolamine Induced Amnesia - Yadav_2018_Front.Pharmacol_9_549
Author(s) : Yadav E , Singh D , Yadav P , Verma A
Ref : Front Pharmacol , 9 :549 , 2018
Abstract : Over recent years, utilization of green synthesized nanomaterials has been widely growing on human body because of its special properties. With the increasing acceptance of nanoparticle approach for various clinical treatments, the biosafety and toxicological effects on the vital organs such as central nervous system, have received more concern. Main focus of this study was to evaluate acute exposure of n-butanol fraction of Prosopis cineraria (L.) Druce hydroethanolic extract (BuPC) and green synthesized zinc oxide nanoparticles of BuPC (ZnOPC) on spatial cognition behavior, and to assess underlying mechanism by estimation of enzymatic antioxidative status along with acetylcholinesterase (AChE) activity in mice brain. Strongest in vitro antioxidant and AChE inhibitory activity exhibiting fraction, BuPC, was examined for inhibition kinetic study by Lineweaver-Burk and Dixon plots. BuPC was further used for fabrication ZnOPC and characterized by UV-visible spectroscopy, Fourier Transform Infrared (FTIR), Field Emission Scanning Electron Microscopy (FESEM), Energy Dispersive X ray (EDX), and Dynamic Light Scattering (DLS) analysis. Old male swiss albino mice were randomly divided into seven groups and treated for 21 days. Subsequently spatial memory was determined by two behavioral models [Elevated plus maze (EPM) and Hebbs William maze (HWM)] and supernatant of brain homogenate was analyzed for enzymatic antioxidant level and AChE inhibitory activity. Zinc content of blood plasma and brain was estimated. Results showed prolonged transfer latency (TL) and time taken to reach reward chamber (TRC) by scopolamine was not ameliorated by the ZnOPC group, whereas BuPC group showed significant reduction in scopolamine induced increase in TL and TRC compared to control and scopolamine treated groups. ZnOPC alleviated enzymatic antioxidant activity and AChE as compared to donepezil and BuPC treated groups. Study concludes that ZnOPC attenuated spatial learning and memory by increase in oxidative stress and decrease in AChE activity at both dose levels. Our results suggest that BuPC exhibited a strong neuroprotective effect on cognitive deficit mice and it may be employed as a strong substance for the treatment of dementia whereas the green synthesized ZnOPC was not proficient to reverse the memory impairment induced by scopolamine.
ESTHER : Yadav_2018_Front.Pharmacol_9_549
PubMedSearch : Yadav_2018_Front.Pharmacol_9_549
PubMedID: 29875670

Title : Beneficial Effect of Protein Tyrosine Phosphatase Inhibitor and Phytoestrogen in Dyslipidemia-Induced Vascular Dementia in Ovariectomized Rats - Verma_2015_J.Stroke.Cerebrovasc.Dis_24_2434
Author(s) : Verma A , Sharma S
Ref : J Stroke Cerebrovasc Dis , 24 :2434 , 2015
Abstract : BACKGROUND: Estrogen deficiency and increase in protein tyrosine phosphatase (PTPase) activity may be a key mechanism in postmenopausal dyslipidemia-induced vascular dysfunction and dementia. Thus, the present study has been designed to investigate the effect of biochanin A (BCA, a phytoestrogen) and sodium orthovanadate (SOV), an inhibitor of PTPase in dyslipidemia-induced vascular dementia in ovariectomized rats.
METHODS: Female Wistar rats were ovariectomized and fed on high fat diet for 4 weeks to produce dyslipidemia. Dyslipidemia was assessed by estimation of serum lipid levels including total cholesterol, triglyceride, HDL, and LDL levels. Dementia was assessed in terms of increase in brain acetylcholinesterase (AChE) activity and attenuation of learning ability (escape latency time) and memory retention (time spent in target quadrant) using Morris water maze. Vascular dysfunction was assessed in terms of attenuation of acetylcholine-induced endothelium-dependent relaxation (isolated carotid ring preparation), mRNA expression of endothelial nitric oxide synthase, and increase in serum thiobarbituric acid reactive species, superoxide anion level. Neurodegeneration was assessed in hippocampus by hematoxylin and eosin staining. BCA (2.5 and 5 mg/kg) and SOV (5 and 10 mg/kg) were administered alone and in low-dose combination to ovariectomized dyslipidemic rats.
RESULTS: BCA (2.5 and 5 mg/kg), SOV (5 and 10 mg/kg), and donepezil (1 mg/kg) significantly improves vascular function, and learning and memory ability and decreases the neuronal cell death, oxidative stress, and AChE in ovariectomized dyslipidemic rats.
CONCLUSIONS: Thus, it may be concluded that BCA and SOV attenuate vascular dysfunction and dementia in dyslipidemic ovariectomized rats.
ESTHER : Verma_2015_J.Stroke.Cerebrovasc.Dis_24_2434
PubMedSearch : Verma_2015_J.Stroke.Cerebrovasc.Dis_24_2434
PubMedID: 26324516

Title : 3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae - Verma_2015_Bioorg.Med.Chem_23_1321
Author(s) : Verma A , Wong DM , Islam R , Tong F , Ghavami M , Mutunga JM , Slebodnick C , Li J , Viayna E , Lam PC , Totrov MM , Bloomquist JR , Carlier PR
Ref : Bioorganic & Medicinal Chemistry , 23 :1321 , 2015
Abstract : To identify potential selective and resistance-breaking mosquitocides against the African malaria vector Anopheles gambiae, we investigated the acetylcholinesterase (AChE) inhibitory and mosquitocidal properties of isoxazol-3-yl dimethylcarbamates (15), and the corresponding 3-oxoisoxazole-2(3H)-dimethylcarboxamide isomers (14). In both series, compounds were found with excellent contact toxicity to wild-type susceptible (G3) strain and multiply resistant (Akron) strain mosquitoes that carry the G119S resistance mutation of AChE. Compounds possessing good to excellent toxicity to Akron strain mosquitoes inhibit the G119S mutant of An. gambiae AChE (AgAChE) with ki values at least 10- to 600-fold higher than that of propoxur, a compound that does not kill Akron mosquitoes at the highest concentration tested. On average, inactivation of WT AgAChE by dimethylcarboxamides 14 was 10-20 fold faster than that of the corresponding isoxazol-3-yl dimethylcarbamates 15. X-ray crystallography of dimethylcarboxamide 14d provided insight into that reactivity, a finding that may explain the inhibitory power of structurally-related inhibitors of hormone-sensitive lipase. Finally, human/An. gambiae AChE inhibition selectivities of these compounds were low, suggesting the need for additional structural modification.
ESTHER : Verma_2015_Bioorg.Med.Chem_23_1321
PubMedSearch : Verma_2015_Bioorg.Med.Chem_23_1321
PubMedID: 25684426

Title : Microbacterium enclense sp. nov., isolated from sediment sample - Mawlankar_2015_Int.J.Syst.Evol.Microbiol_65_2064
Author(s) : Mawlankar RR , Mual P , Sonalkar VV , Thorat MN , Verma A , Srinivasan K , Dastager SG
Ref : Int J Syst Evol Microbiol , 65 :2064 , 2015
Abstract : A novel bacterium (strain NIO-1002(T)) belonging to the genus Microbacterium was isolated from a marine sediment sample in Chorao Island, Goa Province, India. Its morphology, physiology, biochemical features and 16S rRNA gene sequence were characterized. Cells of this strain were Gram-stain-positive, non-motile, non-spore-forming rods that formed yellow-pigmented colonies. It grew in 0-12% (w/v) NaCl and at 25-37 degrees C, with optimal growth at 30 degrees C. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain NIO-1002(T) is associated with members of the genus Microbacterium, with highest sequence similarity with Microbacterium hominis CIP 105731(T) (98.1%) and Microbacterium testaceum KCTC 9103(T) (98.0%). Within the phylogenetic tree, this novel strain shared a branching point with M. hominis CIP 105731(T). The DNA G+C content was 66.5 mol% and DNA-DNA hybridization relatedness between NIO-1002(T), M. hominis CIP 105731(T) and M. testaceum KCTC 9103(T) was 39.0 +/- 2.0% and 41.0 +/- 2.0%, respectively. The major fatty acids were ai-C15 : 0, i-C16 : 0 and ai-C17 : 0 and the diamino acid in the cell-wall peptidoglycan of NIO-1002(T) was lysine. Data obtained from DNA-DNA hybridization and chemotaxonomic phenotypic analysis support the conclusion that strain NIO-1002(T) represents a novel species within the genus Microbacterium. The name Microbacterium enclense sp. nov. is proposed, with NIO-1002(T) ( = NCIM 5454(T) = DSM 25125(T) = CCTCC AB 2011120(T)) as the type strain.
ESTHER : Mawlankar_2015_Int.J.Syst.Evol.Microbiol_65_2064
PubMedSearch : Mawlankar_2015_Int.J.Syst.Evol.Microbiol_65_2064
PubMedID: 25829331
Gene_locus related to this paper: 9mico-a0a0v8gnx9

Title : Current acetylcholinesterase-inhibitors: a neuroinformatics perspective - Shaikh_2014_CNS.Neurol.Disord.Drug.Targets_13_391
Author(s) : Shaikh S , Verma A , Siddiqui S , Ahmad SS , Rizvi SM , Shakil S , Biswas D , Singh D , Siddiqui MH , Tabrez S , Kamal MA
Ref : CNS Neurol Disord Drug Targets , 13 :391 , 2014
Abstract : This review presents a concise update on the inhibitors of the neuroenzyme, acetylcholinesterase (AChE; EC 3.1.1.7). AChE is a serine protease, which hydrolyses the neurotransmitter, acetylcholine into acetate and choline thereby terminating neurotransmission. Molecular interactions (mode of binding to the target enzyme), clinical applications and limitations have been summarized for each of the inhibitors discussed. Traditional inhibitors (e.g. physostigmine, tacrine, donepezil, rivastigmine etc.) as well as novel inhibitors like various physostigmine-derivatives have been covered. This is followed by a short glimpse on inhibitors derived from nature (e.g. Huperzine A and B, Galangin). Also, a discussion on 'hybrid of pre-existing drugs' has been incorporated. Furthermore, current status of therapeutic applications of AChEinhibitors has also been summarized.
ESTHER : Shaikh_2014_CNS.Neurol.Disord.Drug.Targets_13_391
PubMedSearch : Shaikh_2014_CNS.Neurol.Disord.Drug.Targets_13_391
PubMedID: 24059296

Title : Select small core structure carbamates exhibit high contact toxicity to carbamate-resistant strain malaria mosquitoes, Anopheles gambiae (Akron) - Wong_2012_PLoS.One_7_e46712
Author(s) : Wong DM , Li J , Chen QH , Han Q , Mutunga JM , Wysinski A , Anderson TD , Ding H , Carpenetti TL , Verma A , Islam R , Paulson SL , Lam PC , Totrov M , Bloomquist JR , Carlier PR
Ref : PLoS ONE , 7 :e46712 , 2012
Abstract : Acetylcholinesterase (AChE) is a proven target for control of the malaria mosquito (Anopheles gambiae). Unfortunately, a single amino acid mutation (G119S) in An. gambiae AChE-1 (AgAChE) confers resistance to the AChE inhibitors currently approved by the World Health Organization for indoor residual spraying. In this report, we describe several carbamate inhibitors that potently inhibit G119S AgAChE and that are contact-toxic to carbamate-resistant An. gambiae. PCR-RFLP analysis was used to confirm that carbamate-susceptible G3 and carbamate-resistant Akron strains of An. gambiae carry wild-type (WT) and G119S AChE, respectively. G119S AgAChE was expressed and purified for the first time, and was shown to have only 3% of the turnover number (k(cat)) of the WT enzyme. Twelve carbamates were then assayed for inhibition of these enzymes. High resistance ratios (>2,500-fold) were observed for carbamates bearing a benzene ring core, consistent with the carbamate-resistant phenotype of the G119S enzyme. Interestingly, resistance ratios for two oxime methylcarbamates, and for five pyrazol-4-yl methylcarbamates were found to be much lower (4- to 65-fold). The toxicities of these carbamates to live G3 and Akron strain An. gambiae were determined. As expected from the enzyme resistance ratios, carbamates bearing a benzene ring core showed low toxicity to Akron strain An. gambiae (LC(50)>5,000 mug/mL). However, one oxime methylcarbamate (aldicarb) and five pyrazol-4-yl methylcarbamates (4a-e) showed good to excellent toxicity to the Akron strain (LC(50) = 32-650 mug/mL). These results suggest that appropriately functionalized "small-core" carbamates could function as a resistance-breaking anticholinesterase insecticides against the malaria mosquito.
ESTHER : Wong_2012_PLoS.One_7_e46712
PubMedSearch : Wong_2012_PLoS.One_7_e46712
PubMedID: 23049714
Gene_locus related to this paper: anoga-ACHE1

Title : Additive effects of a cholinesterase inhibitor and a histamine inverse agonist on scopolamine deficits in humans - Cho_2011_Psychopharmacology.(Berl)_218_513
Author(s) : Cho W , Maruff P , Connell J , Gargano C , Calder N , Doran S , Fox-Bosetti S , Hassan A , Renger J , Herman G , Lines C , Verma A
Ref : Psychopharmacology (Berl) , 218 :513 , 2011
Abstract : RATIONALE: Enhancement of histaminergic neurotransmission or histaminergic plus cholinergic neurotransmission may represent novel strategies for improving cognition in Alzheimer's disease. OBJECTIVE: To evaluate the effects of a novel histamine H3 receptor inverse agonist (MK-3134), an acetylcholinesterase inhibitor (donepezil), and their combination in attenuating the cognitive impairment associated with scopolamine. METHODS: Thirty-one subjects were randomized, and 28 completed this double-blind, placebo-controlled, five-period crossover study. Cognition was assessed using the Groton Maze Learning Task (GMLT) as the primary outcome measure. The two primary hypotheses were that donepezil 10 mg and MK-3134 25 mg, respectively, would attenuate scopolamine (0.5 mg)-induced impairment as measured by the GMLT over the first 12 h after scopolamine administration (AUC(1-12) (h)). A secondary hypothesis was that the combination of donepezil and MK-3134 would attenuate scopolamine-induced cognitive impairment to a greater extent than either agent alone as measured by the GMLT AUC(1-12 h). RESULTS: The primary and secondary hypotheses were not met. Upon examining the time course of the scopolamine effects (an exploratory objective), peak effects were generally observed around 2 h after scopolamine administration. Administration of MK-3134 or donepezil improved performance on the GMLT at the 2-h time point, rather than AUC(1-12 h), compared with scopolamine alone. Moreover, it appeared that the combination of MK-3134 and donepezil blunted the scopolamine effect to a greater extent than either drug alone. CONCLUSIONS: Exploratory analyses provide evidence for cognitive improvement through inverse agonism of the H3 histamine receptor and for cooperation between human cholinergic and histaminergic neurotransmitter systems. (ClinicalTrials.gov trial registration number: NCT01181310).
ESTHER : Cho_2011_Psychopharmacology.(Berl)_218_513
PubMedSearch : Cho_2011_Psychopharmacology.(Berl)_218_513
PubMedID: 21644059

Title : Paradoxical DNA repair and peroxide resistance gene conservation in Bacillus pumilus SAFR-032 - Gioia_2007_PLoS.One_2_e928
Author(s) : Gioia J , Yerrapragada S , Qin X , Jiang H , Igboeli OC , Muzny D , Dugan-Rocha S , Ding Y , Hawes A , Liu W , Perez L , Kovar C , Dinh H , Lee S , Nazareth L , Blyth P , Holder M , Buhay C , Tirumalai MR , Liu Y , Dasgupta I , Bokhetache L , Fujita M , Karouia F , Eswara Moorthy P , Siefert J , Uzman A , Buzumbo P , Verma A , Zwiya H , McWilliams BD , Olowu A , Clinkenbeard KD , Newcombe D , Golebiewski L , Petrosino JF , Nicholson WL , Fox GE , Venkateswaran K , Highlander SK , Weinstock GM
Ref : PLoS ONE , 2 :e928 , 2007
Abstract : BACKGROUND: Bacillus spores are notoriously resistant to unfavorable conditions such as UV radiation, gamma-radiation, H2O2, desiccation, chemical disinfection, or starvation. Bacillus pumilus SAFR-032 survives standard decontamination procedures of the Jet Propulsion Lab spacecraft assembly facility, and both spores and vegetative cells of this strain exhibit elevated resistance to UV radiation and H2O2 compared to other Bacillus species. PRINCIPAL FINDINGS: The genome of B. pumilus SAFR-032 was sequenced and annotated. Lists of genes relevant to DNA repair and the oxidative stress response were generated and compared to B. subtilis and B. licheniformis. Differences in conservation of genes, gene order, and protein sequences are highlighted because they potentially explain the extreme resistance phenotype of B. pumilus. The B. pumilus genome includes genes not found in B. subtilis or B. licheniformis and conserved genes with sequence divergence, but paradoxically lacks several genes that function in UV or H2O2 resistance in other Bacillus species. SIGNIFICANCE: This study identifies several candidate genes for further research into UV and H2O2 resistance. These findings will help explain the resistance of B. pumilus and are applicable to understanding sterilization survival strategies of microbes.
ESTHER : Gioia_2007_PLoS.One_2_e928
PubMedSearch : Gioia_2007_PLoS.One_2_e928
PubMedID: 17895969
Gene_locus related to this paper: bacp2-a8f9m3 , bacp2-a8fa85 , bacp2-a8fgk8 , bacp2-a8fhg9 , bacp2-a8fjc9 , bacpu-AXE , bacpu-b4af62 , bacpu-b4ail3 , bacpu-b4ann4 , bacpu-b4apa9 , bacp2-a8f983 , bacp2-a8fgz0

Title : Magnetic resonance imaging changes in a case of extra-pyramidal syndrome after acute organophosphate poisoning - Goel_2006_Neurol.India_54_207
Author(s) : Goel D , Singhal A , Srivastav RK , Verma A , Lamba A
Ref : Neurol India , 54 :207 , 2006
Abstract : Distal symmetrical polyneuropathy and neuromuscular weakness is common neurological problem in recovery phase of acute organophosphate (OP) poisoning. Various types of extra pyramidal syndromes are uncommon sequel after OP poisoning. These are reported to be reversible within few weeks and characteristically associated with normal magnetic resonance imaging (MRI). In this report we are presenting a case with extra pyramidal syndrome after acute OP poisoning with few interesting MRI changes in striatum.
ESTHER : Goel_2006_Neurol.India_54_207
PubMedSearch : Goel_2006_Neurol.India_54_207
PubMedID: 16804273